Functionalized Naphthalimide-4-aminoquinoline Conjugates as Promising Antiplasmodials, with Mechanistic Insights

Abstract

A series of 25 conjugates has been synthesized to evaluate their antiplasmodial potency and cytotoxicity against the chloroquine resistant (CQR) W2 strain of <i>P. falciparum</i> and Vero kidney cell lines, respectively. Most of the compounds showed IC₅₀ values in the lower nM range and proved to be many fold more active than chloroquine (CQ). The studies were extended to decipher modes of action using techniques including UV-vis absorption, NMR titrations, and mass spectrometry, and conclusions were strengthened by docking and density functional theory (DFT) simulations. The most active compound, with IC₅₀ 15 nM and selectivity index >4000, proved to be an interesting template for antimalarial drug discovery. To the best of our knowledge this is the first report of a potent naphthalimide based antiplasmodial conjugate.